The major challenge facing TBV development is to find a highly safe formulation that induces sustained high antibody responses. LMIV has demonstrated that conjugating Pfs25 and Pfs230 with carrier protein ExoProtein A (EPA) of Pseudomonas aeruginosa greatly enhances the immunogenicity of the recombinant TBVs and has shown to be safe with the adjuvant Alhydrogel, but may need a stronger adjuvant such as AS01 to achieve the antibody responses needed to block transmission. Highlighted in this years summary are results from our publications: Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission blocking vaccine against Plasmodium falciparum: a randomized, double-blind, comparator-controlled, dose-escalation study in healthy malaria exposed Malian adults. Pfs25H-EPA is a protein-protein conjugate transmission-blocking vaccine against Plasmodium falciparum that is safe and induces functional antibodies in malaria-naive individuals. In this field trial, we assessed Pfs25H-EPA/Alhydrogel for safety and functional immunogenicity in Malian adults. The primary outcomes were safety and tolerability for all vaccinees. The secondary outcome measure was immunogenicity 14 days after vaccination in the per-protocol population, as confirmed by the presence of antibodies against Pfs25H measured by ELISA IgG and antibody functionality assessed by standard membrane feeding assays and by direct skin feeding assays. Pfs25H-EPA/Alhydrogel was well tolerated and induced significant serum activity by standard membrane feeding assays but transmission blocking activity was not confirmed by weekly direct skin feed. This activity required four doses, and titres decreased rapidly after the fourth dose. This publication reported the first field trial of a malaria transmission blocking vaccine, establishing a clinical benchmark for further improvement, as well as new approaches to assess the activity of such vaccines using direct skin feeding assays. In addition to these published results, we have seen progress in our other trials of Pfs25 and Pfs230 vaccines. Pfs230D1M-EPA/Alhydrogel and Pfs25M-EPA/Alhydrogel in Healthy US and Malian Adults (NIAID protocol 15-I-0044) The phase 1 study of the safety, tolerability, immunogenicity, and functional activity of Pfs230D1M-EPA/Alhydrogel (Pfs230) and Pfs25M-EPA/Alhydrogel (Pfs25M) in adults started in the US (n=35) in Dec 2014 and in Mali (n=225) in Apr 2015. The US portion of the study was to evaluate safety and tolerability with only 2 vaccinations at 0, 1 month of increasing doses of Pfs25M and Pfs230 given alone or in combination prior to moving to Mali for further safety, immunogenicity, and functional activity evaluation during which time those in the functional activity cohort received 4 doses at 0, 1, 6 months and a booster at 18 months during the subsequent malaria season. The results demonstrate that Pfs230 is superior to Pfs25 as a protein-protein conjugate vaccine candidate when using Alhydrogel as an adjuvant. Further, the addition of Pfs25 to Pfs230 does not enhance vaccine activity measured by standard membrane feeding assay. Most important, Pfs230 is able to induce significant functional activity in some volunteers after only 2 doses, and major improvement over the results previous seen with Pfs25 alone vaccines. However, further analysis indicated that the induced antibodies were not durable. Thus to improve the longevity of the functional activity, we forged a new collaboration with GSK to use a more potent adjuvant, AS01. Pfs230D1M-EPA/AS01 and Pfs25M-EPA/AS01 in Healthy Malian Adults (NIAID protocol 17-I-N006) The phase 1 study of the safety, tolerability, immunogenicity, and functional activity of Pfs25M-EPA/AS01 (Pfs25M) and Pfs230D1M-EPA/AS01 (Pfs230) started recruitment for the Pilot Safety Phase dose-escalation in Sotuba in Dec 2016. Vaccinations were scheduled at All 3 vaccinations (0, 1, and 6 months) for all Arms enrolled in the Safety Pilot Phase of the study were completed. Results from the Pilot Safety Phase showed that Pfs230D1M-EPA/AS01 (Pfs230) alone exhibited higher antibody titers and functional activity that did not improve with additional of Pfs25M-EPA/AS01 (Pfs25M). As a result, the study continued with only administration of Pfs230D1M-EPA/AS01. Recruitment for the randomized double-blind portion of the study (Main Phase) started in Feb 2017, with pre-emptive treatment with Artemether LumefantrineL, en bloc randomization with stratification by village., and 2 of 3 vaccinations being completed in the 0, 1, 6-month vaccination schedule to date. The third and final vaccination was completed in Aug/Sept 2017 and beginning in Sep 2017 subjects in the Main Phase underwent 12 weeks of DSF (twice a week) for a total of 24 mosquito feeds. In August 2018, 163 participants re-enrolled and were vaccinated in Bancoumana and Doneguebougou villages, with 16 weeks of DSF assays planned to be completed in December 2018. The results to date in this study indicate that antibody titers are increased substantially with Pfs230D1M-EPA/AS01 and Pfs25M-EPA/AS01 over those achieved with Alyhdrogel-adjuvanted vaccines., In addition, that the functional activity induced by Pfs230D1M-EPA/AS01 is superior to Pfs25M-EPA/AS01 and is not improved by the addition of Pfs25M-EPA/AS01, and that significant functional activity can be achieved after only 2 doses of Pfs230D1M-EPA/AS01.